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PHARMACOLOGY OF DRUGS USED IN CANCER: AN OVERVIEW Sara Fawaz Alsharhan Pharm.D candidate, KSU May 2014 Outline • Introduction • Chemotherapy classes Alkylating agents Antimetabolites Antimitotics Cytotoxic antibiotics Platinum compounds Others • Targeted agents Introduction • The National Cancer Institute defines chemotherapy as drugs that treat cancer cells. • It kills cancer cells by damaging DNA, interfering with DNA synthesis, or inhibiting cell division. Introduction • Chemotherapy agents are classified by their effect on the cell cycle or their mechanism of action. • They can be classified also as phase specific agents or phase non specific agents. Cell cycle and effects of representative agents on phases of the cell cycle Introduction • After understanding the mechanisms of the unregulated growth of cells and the ability to invade tissues and metastasize, targeted agents were designed (monoclonal antibodies and tyrosine kinase inhibitors). • Hormone therapies inhibit tumor growth by blocking the receptors or by eliminating the endogenous hormone feeding the tumor. Chemotherapy classes Alkylating agents Platinum compounds Mitotic inhibitors Antimetabolites Cytotoxic antibiotics Alkylating agents • Alkylating agents involve reactions with guanine in DNA. • These agents add methyl or other alkyl groups onto molecules where they do not belong. • This in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents Agent Subclass Route Pharmacokinetic Major toxicities Busulfan Alkyl sulfonate IV, PO • Well absorbed orally • Metabolized by liver extensively • Metabolites eliminated renaly • Myelosuppression • Pulmonary fibrosis • Hyperpigmentation • Hepatic dysfunction • Suppression of testicular, ovarian, and adrenal function • Seizures and venoocclusive disease with high dose Melphalan Nitrogen mustard IV, PO • Variable oral absorption on empty stomach • Elimination by hydrolysis • Minimal renal elimination • Myelosuppression • Alopecia • Hepatic dysfunction • Nausea/vomiting • Pulmonary fibrosis Alkylating agents Agent Subclass Route Pharmacokinetic Major toxicities Chlorambucil Nitrogen mustard PO • Well absorbed • Protein bound • Metabolized by liver extensively • Metabolites spontaneously degrade • Minimal renal elimination • Myelosuppression; • Tremor • Twitching • Myoclonia • Agitation • Ataxia • Hallucinations • Pulmonary fibrosis • Hepatic dysfunction Cyclophosphamide Nitrogen mustard IV, PO • Well absorbed with food • Activated in liver • Eliminated by kidneys • Myelosuppression • Hemorrhagic cystitis • Nausea/vomiting • Alopecia • Cardiomyopathy • Interstitial pneumonitis • SIADH Alkylating agents Agent Subclass Route Pharmacokinetic Major toxicities Ifosfamide Nitrogen mustard IV • Activated in liver • Renal elimination • Myelosuppression • Hemorrhagic cystitis(should be administered with MESNA) • Somnolence, confusion, hallucinations • Nausea/vomiting • Alopecia Carmustine Nitrosourea IV • Crosses the blood–brain barrier effectively; • Renal elimination • Myelosuppression • Pulmonary toxicity • Nausea\Vomiting • Hepatic and renal dysfunction • Venous irritant Lomustine Nitrosourea PO Crosses the blood– • Myelosuppression brain barrier • Nausea/vomiting effectively • Pulmonary fibrosis • Hepatic and renal dysfunction Antimetabolites Purine analogs Antimetabolites Antimetabolites- Folic acid antagonists Agent MOA Route Pharmacokinetic Methotrexate • Inhibts DHFR • Reduce folates IV, PO • Variable absorption on empty stomach and may decreased by milk rich food • Response may decreased by folate • Renal elimination Major toxicities • Myelosuppression • Renal and hepatic dysfunction • Mucositis • Pulmonary toxicity • Neurotoxicity Antimetabolites- Purine analogs Agent MOA Route Pharmacokinetic Major toxicities Mercaptopurine Inhibits the first step of the de novo purine synthesis PO • Absorption highly variable on empty stomach • Hepatic and GI mucosa metabolism • Hepatic elimination • Myelosuppression • Anorexia • Nausea/vomiting • Hepatic dysfunction PO • Mean bioavailability 30% • Hepatic metabolism •Minimal excretion in urine • Myelosuppression • Hepatotoxicity (including venoocclusive disease) • Hyperuricemia • Anorexia, mild nausea and stomatitis Thioguanine Antimetabolites- Pyrimidine analogs Agent MOA Route Pharmacokinetic Major toxicities Capecitabine Prodrug metabolized to fluorouracil; PO • Well absorbed • Moderately protein bound • Extensive hepatic metabolism • Renal elimination • Nausea/vomiting • Stomatitis • Hand-foot syndrome • Myelosuppression • Anorexia Fluorouracil • Incorporates into RNA and interferes with RNA function • Inhibits TS IV • Hepatic metabolism • Minimal renal elimination • Mucositis • Diarrhea • Myelosuppression • Dermatologic • Nausealvomiting • Hand foot syndrome Gemcitabine Inhibits DNA and RNA synthesis by inhibiting ribonucleotide reductase IV • Intracellular metabolism • Primary renal elimination • Myelosuppression • Flu like syndrome • Nausea/vomiting • Edema Antimtotics Antimitotics Agent MOA Route Pharmacokinetic Major toxicities Vinblastine • Bind to tubulin • Interfering with microtubule assembly • Mitotic spindle formation IV • Hepatic metabolism • Biliary elimination • Myelosuppression • CNS toxicity • Nausea/vomiting • Vesicant • Hepatic metabolism • Fecal elimination •Neurotoxicity (sensory and motor) • Autonomic neuropathies • Constipation • SIADH • Vesicant Vincristine Vinorelbine • Leukopenia • Neurotoxicity • Vesicant Cytotoxic antibiotics • Anthracyclines: Stabilizes the cleavable complex between topoisomerase II and DNA, causing single- and doublestrand DNA breaks; forms oxygen free radicals. Cytotoxic antibiotics Agent Pharmacokinetic Daunorubicin • Extensive binding to tissues • Hepatic metabolism • Moderate biliary excretion • Minimal renal elimination Doxorubicin Major toxicities • Myelosuppression • Mucositis • Alopecia • Cumulative cardioctoxicity • Vesicant • Nausea/vomiting and diarrhea • Headache • Edema • Neuropathy • Back pain • Dyspnea, • Hand-foot syndrome • Myelosuppression • mucositis • Alopecia • Cumulative cardiactoxicity • Vesicant • Nausea/vomiting • fatigue • Stomatitis • Rash, hand-foot syndrome Cytotoxic antibiotics Agent Pharmacokinetic Major toxicities Epirubicin • Highly protein bound • Hepatic metabolism • Moderate biliary excretion • Minimal renal elimination • Myelosuppression • Mucositis • Alopecia • Cumulative cardiactoxicity • Vesicant Idarubicin • Extensive extrahepatic metabolism • Primarily biliary excretion • Minimal renal elimination • Myelosuppression • Mucositis • Anorexia, nausea, vomiting, diarrhea • Fever •A lopecia • Vesicant Bleomycin • Enzymatic degradation by a cytosolic cysteine proteinase • Widely distributed in normal tissues except lung and skin • Renal elimination • Erythema, • Hyperpigmentation • Pulmonarytoxicity • Fever, chills • Vomiting Platinum compounds • Mechanism of action: React with nucleophilic sites on DNA causing DNA cross-links. Platinum compounds Agent Pharmacokinetic • Myelosuppression • Nausea\vomiting • Peripheral neuropathy Carboplatin Cisplatin Oxaliplatin Major toxicities Elimination primarily renal • Highly protein bound • Renal elimination • Nephrotoxicity • Nausea\vomiting • Peripheral neuropathy • Ototoxicity • Electrolyte disturbances • Anaphylactic reactions • Peripheral neuropathy, sensitivity to cold, jaw spasm, dysphagia • Nausea, vomiting, diarrhea, fatigue • Pulmonary fibrosis Others Agent MOA Route Pharmacokinetic Major toxicities Etoposide • Inhibits topoisomerase II • Stabilizing the cleavable complex • Breakage of double-strand DNA IV and PO • Variable oral absorption • Highly protein bound • Moderate renal elimination • Minimal bile and fecal elimination • Myelosuppression • Nausea, vomiting • Alopecia • Mucositis • Hypotension (related to rapid infusion) • Hypersensitivity reactions • Fever • Bronchospasm Asparaginase • Hydrolyzes serum asparagines to nonfunctional aspartic acid and ammonia • Depriving tumor cells of a necessary amino acid IV Not well documented • Allergic reactions • Reduction of clotting factors • Pancreatitis • Hepatic and renal dysfunction Targeted agents Monoclonal antibodies • Unlike traditional chemotherapy, they selectively target receptors or their ligands known to potentiate cancer pathways. • As result, they minimize toxicity to noncancer cells. Tyrosine kinase inhibitors • Small molecules that directly inhibit tyrosine kinase activation by competing with ATP for biding to the intracellular tyrosine kinase. • They include inhibiting cells that may not overexpress the receptors on their surface or have mutated form of the receptor that result in its activation. Summary References • Brian K., et al. (2013). Applied Therapeutics.10th ed. Pheladelphia: 2126-2146. • Lexi-comp, 2014 • Drugs.com THANK YOU!
